The Association Between Oxidative Stress Alleviation via Sulforaphane-Induced Nrf2-HO-1/NQO-1 Signaling Pathway Activation and Chronic Renal Allograft Dysfunction Improvement

Abstract

Background/Aims: Chronic renal allograft dysfunction (CRAD) is a leading cause of long-term renal allograft loss. Oxidative stress may account for the nonspecific interstitial fibrosis and tubular atrophy that occur in CRAD. An antioxidant intervention via Nrf2 signaling pathway activation might be a promising therapy for some kidney diseases. The present paper investigates whether there is an association between oxidative stress alleviation via sulforaphane-induced Nrf2-HO-1/NQO-1 signaling pathway activation and CRAD improvement. Methods: F344 rat kidneys were orthotopically transplanted into Lewis rat recipients to establish CRAD models. Sulforaphane was administered at 1.5 mg/kg intraperitoneally once daily. Renal function and 24-hour urinary protein were monitored for variations for 24 weeks after transplantation. After 24 weeks, renal histopathology was evaluated according to the Banff criteria after hematoxylin and eosin, Masson’s trichrome and periodic acid-Schiff stainings. Additionally, intrarenal oxidative stress was assessed by the indicators malondialdehyde, 8-isoprostane, oxidized-low density lipoprotein and 8-hydroxy-2’-deoxyguanosine, as well as the activity levels of the antioxidant enzymes total superoxide dismutase, catalase, glutathione peroxidase, glutathione reductase and γ-glutamylcysteine synthetase. Nrf2, HO-1 and NQO-1 expression levels were determined via immunohistochemical and Western blot analyses. Results: The sulforaphane-induced Nrf2-HO-1/NQO-1 signaling pathway activation, as demonstrated by immunohistochemical and Western blot analyses, delayed the progression of serum creatinine and blood urea nitrogen, particularly lowering the 24-hour urinary protein levels of CRAD. The semi-quantified histopathological changes were also alleviated. Evidence of oxidative stress alleviation, as indicated by a concurrent decrease in the indicators and sustained levels of antioxidant enzymes activity, was found in the renal allografts after sulforaphane intervention. Conclusion: Oxidative stress alleviation caused by continuous sulforaphane-induced Nrf2-HO-1/NQO-1 signaling pathway activation is associated with functional and morphological improvements of CRAD.

Sodium Tanshinone IIA Sulfonate Attenuates Erectile Dysfunction in Rats with Hyperlipidemia

“…HO-1, the best known downstream effector of Nrf2, is regarded as one of the most important intracellular antioxidant mechanisms [11]. Activation of the Nrf2/HO-1 antioxidant pathway contributes to protection from a variety of human diseases [11,20,21]. The present study found that hyperlipidemia increases the protein levels of Nrf2 and HO-1 in the penile tissue, which is reflexively activated when suffering from external oxidative stress.…”

“…However, remarkable increases in the SOD and GSH and noteworthy reduction in MDA were observed after treatment with STS. Based on these experimental results, it is demonstrated that STS Nrf2 is a key modulator of redox balance and signaling, which drives the expression of a battery of genes that protect against oxidative stress, including GSH, SOD, and HO-1 [20]. HO-1, the best known downstream effector of Nrf2, is regarded as one of the most important intracellular antioxidant mechanisms [11].…”

“…Under basal conditions, the activity of Nrf2 is inhibited by Keap1, and upon exposure of cells to oxidative stress, Nrf2 translocates from the cytoplasm to the nucleus and transactivates phase II detoxifying and antioxidant genes [20]. The Nrf2 pathway is vital for the antioxidative response.…”

Naturally Derived Heme-Oxygenase 1 Inducers and Their Therapeutic Application to Immune-Mediated Diseases

“…Sulforaphane, a naturally occurring ITC from broccoli, has been demonstrated to attenuate cell damage induced by 1-methyl-4-phenyl pyridine ion (MPP+) in PC12 cells by reversing the reduced expression of Nrf2, HO-1, and NAD(P)H-quinone oxidoreductase (NQO1) (217). The beneficial effect of SFN-induced Nrf2-HO-1/NQO-1 signaling pathway activation was also demonstrated in chronic renal allograft dysfunction (Figure 1) (218). Furthermore, SFN suppresses T H 17 response on untransformed human T cells by decreasing GSH and the accumulation of ROS (219).…”

<p>Protective Effect of Pravastatin on Myocardial Ischemia Reperfusion Injury by Regulation of the miR-93/Nrf2/ARE Signal Pathway</p>

“…HO-1 and NQO1 are landmark target genes in a series of antioxidant enzyme and detoxifying enzyme genes regulated in the middle and lower reaches of Nrf2 pathway. 28,29 NQO1 is ubiquitous in eukaryotic cells and has strong antioxidant properties, which can prevent oxidation-reduction reactions and oxidative stress reactions of quinones. 30 HO-1 can inhibit various inflammation and oxidation reactions, maintain platelet aggregation and vascular tension, and has protective effect on I/R.…”